The cause of peptic ulcer disease was, for many years, focused on the role of gastric acid in the genesis of peptic ulceration. It was found that suppression of acid production with histamine 2 (H2)—receptor antagonists was effective in healing acute ulcers, but the recurrence rate during the first year could be as high as 90%. Unfortunately, a misconception about the cause produced treatments that may have been effective in healing the ulcers but could not cure the disease.
Eventually, an infectious agent as the cause began to be explored after the isolation of gram-negative spiral-shaped bacteria from biopsy specimens obtained from human subjects with gastritis and peptic ulcers was reported. See Marshall B. J. and Warren J. R., Unidentified curved bacilli on gastric epithelium in active chronic gastritis, Lancet (i):1311-1315 (1984). The infectious agent was initially identified as Campylobacter pyloridis. Subsequent studies have confirmed that this bacterium, currently referred to as Helicobacter pylori (H. pylori), is a major cause of chronic diffuse superficial (type B) gastritis and gastroduodenal ulcer disease. Further evidence to support the role of H. pylori comes from studies using human volunteers that were challenged with H. pylori in order to fulfill Koch's postulates. See Marshall B. J., et al., Med. J. Aust. 142: 436-439 (1985); and Morris A., et al., Am. J. Gastroenterol. 82: 192-199 (1987).
H. pylori bacteria infect more than 50% of the world's human population. See Mitchell, H. M., Curr. Top. Microbiol. Immunol., 241:11-30 (1999). However, it is not understood why many individuals who have been infected for years do not develop any symptoms of gastritis or ulcer disease while others do. There is also a reported connection between H. pylori infection and the development of gastric carcinoma. See Parsonnett J., N. Engl. J. Med. 325:1127-1131 (1991) and Nomura A., et al., N. Engl. J. Med.; 325:1132-1136 (1991). It is now fairly clear that H. pylori infections are responsible for the onset of chronic superficial gastritis, chronic active gastritis, peptic ulcers and gastric cancer. See Parsonnet et al, N. Engl. J. Med., 330:1267-1271 (1994). Consequently, this gastric bacterium has been classified as a category 1 (definite) human carcinogen. See Labigne, A. et al., Infect. Agent Dis., 5:191-202 (1996).
The leading treatment of H. pylori infection in humans is typically carried out by combining one proton pump inhibitor and two antibiotics. See Unge, P. Curr. Top. Microbiol Immunol., 241:261-300 (1999). This combination therapy must be maintained for a week or two, and it can eliminate the infection in 80 to 90% of those treated. See Unge, P. Curr. Top. Microbiol. Immunol., 241:261-300 (1999). Even though antibiotic treatment is effective, there are problems associated with its use. Compliance with the antibiotic treatment regimen is a problem area for antibiotic treatment of H. pylori infection because of the large number of pills and the frequency of administration that are required. See Bell, G. D. et al., Ailment Pharmacol. Ther. 6:427-35 (1992). A more troubling treatment issue involves the emergence of strains of H. pylori that are resistant to the most commonly prescribed antibiotics. Antibiotic resistance is becoming a frequently reported limitation to successful treatment of H. pylori infections. See Graham, D. Y., Gastroenterology 115:1272-77 (1998). Finally, treatment of H. pylori with antibiotic therapies is only offered to those infected patients who are currently showing obvious symptoms, thus the vast majority of asymptomatic people are left untreated awaiting the development of chronic gastritis and eventually gastric cancer.
An effective immunogenic composition to prevent infection would overcome many of the problems and limitations associated with antibiotic based treatments of H. pylori infection. Numerous immunogenic composition candidates have been explored for use in inducing protection against H. pylori infection. Several H. pylori antigens, due to their role in the bacterial life cycle, have been investigated as possible subunit immunogens. Numerous H. pylori immunogens have been described including urease, vacuolating cytotoxin (VacA), cytotoxin associated gene A (cagA) and neutrophil activating protein (NAP), and yet, to date there is no immunogenic composition available for either preventing infection with H. pylori or for therapeutically treating those infected. See Giudice, G. D. et al., Annu. Rev. Immunol., 19:523-563 (2001), the disclosure of which is hereby incorporated by reference in its entirety. A need exists for safe and protective immunogens and immunization strategies for preventing infection with H. pylori and for therapeutically treating infected people.